Hypertrophic cardiomyopathy (HCM) is an inherited heart disease. It is the most common cause of sudden death (SD) in otherwise healthy young individuals. Many HCM patients have left ventricular (LV) outflow obstruction. We have demonstrated that DDD pacemaker therapy improves symptoms and relieves the obstruction in patients with drug-refractory symptoms. This novel therapy is therefore an attractive alternative to cardiac surgery. Although arrhythmias are the most common cause of SD in adults with HCM, we have determined that myocardial ischemia, often silent, is the most common cause of syncope and cardiac arrest in young HCM patients. We have identified 12 distinct mutations in the beta- myosin heavy chain (betaMHC) gene located on chromosome 14, in 16 unrelated kindreds, and estimate that in about 20% of HCM it is caused by mutations in this gene. We have excluded the betaMHC gene locus, and two other novel loci, in 4 large families. We therefore suspect that there are numerous genes that cause HCM to be identified. Molecular markers have been used to identify individuals without LV hypertrophy but with symptoms and arrhythmias caused by aMHC gene mutations. Detailed clinical evaluations indicate that the natural history of the disease is in part determined by the specific mutation. We have demonstrated that mutant messenger RNA and beta myosin are present in skeletal muscle of affected patients. Skeletal muscle myofibers containing mutant beta- myosin have been shown to have abnormal contractile properties. Beta- myosin purified from skeletal muscle of patients with distinct betaMHC gene mutations has been shown to have abnormal function in an in-vitro motility assay. Histochemical analyses show that 60% of patients with betaMHC gene mutations have skeletal myopathy--specifically, "central core disease", a very rare, nonprogressive myopathy characterized by loss of mitochondria from the center of some of the slow myofibers.